The present invention relates to certain novel piperazine derivatives having protracted uro-selective xcex11-adrenoceptor antagonistic activity exceeding those of previously described compounds. The compounds of the present invention hold promise for treating benign prostatic hyperplasia (BPH). This invention also relates to methods for making the novel compounds, pharmaceutical compositions containing the compounds, and methods of treating benign prostatic hyperplasia using the compounds.
A review in J. Med. Chem., 1997, V.40, No.9, pp. 1292-1315, describes the most important pharmacological options available at present in the treatment of benign prostatic hyperplasia. The two most successful therapies are based on xcex1-adrenergic receptor antagonism and androgen levels modulation by 5xcex1-reductase inhibitors. 5xcex1-reductase inhibitors are of limited effectiveness in terms of immediate symptomatic and urodynamic relief. xcex11-antagonists appear to be much more effective and provide immediate subjective symptomatic improvements and are therefore the preferred modalities of treatment in the control of benign prostrate hypertrophy. xcex11-adrenoceptors are also present in blood vessels and play an important role in the regulation of blood pressure. Thus, xcex11-adrenoceptor antagonists are of particular importance as they were originally developed as antihypertensive agents and are likely also to have a beneficial effect on lipid dysfunction and insulin resistance, which are commonly associated with essential hypertension.
The more important of the xcex11-adrenoceptor antagonists which are currently used in the management of BPH are shown below. 
However, most of these known drugs are associated with vascular side effects (e.g., postural hypertension, syncope, dizziness, headaches, etc.) due to lack of selectivity of action between prostatic and vascular xcex11-adrenoceptors. Clearly, xcex11-adrenoceptor antagonists which have inherently greater selectivity for prostatic xcex11-adrenoceptors offer the potential of increased urodynamic benefits. This underscores the importance of the discovery of prostate-selective xcex11-adrenoceptor antagonists which will confer urodynamic improvement without the side effects associated with existing drugs.
Recently, it has been demonstrated that the prostate tissue of higher species like man and dog is overvalued by low affinity xcex11A-adrenoceptor subtype. This makes it possible to develop agents with selective action against these pathological urodynamic states. The present invention is directed to the development of novel xcex11-antagonists, namely, a new class of piperazine compounds, with greater selectivity of action against xcex11A-adrenoceptors and which would thus offer selective relief for prostate hypertrophy as well as essential hypertension.
There are many descriptions in the literature of the pharmacological activities associated with phenyl piperazines. Eur. J. Med. Chem.-Chimica Therapeutica, 1977, V. 12, No. 2, pp. 173-176, describes substituted trifluoromethyl phenyl piperazines having cyclo-imido alkyl side chains shown below as anorectic agents with no CNS side effects. 
The synthesis and pharmacology of some 2-[3-(4-aryl-1-piperazinyl)propyl]-1H-benz[de]isoquinolin-1,3-(2H)-diones/2,5-pyrrolidinediones (J. Indian Chem. Soc., 1986, V. LXIII, pp.529-530), of N-(N4-aryl-N1-piperozinylmethyl)-4-(4xe2x80x2-methoxyphenyl)piperidine-2,6-diones(J. Indian Chem. Soc., 1978, v. LV, pp.819-821), and of N-(N4-arylpiperazinylalkyl)- phthalimides (J. Indian Chem. Soc., 1979, V. LVI, pp. 1002-1005), as shown below, have been reported. The compounds were shown to exhibit antihypertensive and CNS depressant activity in experimental animals. 
However, in those papers there is no mention of the adrenoceptor blocking activity of these compounds, and thus their usefulness in the treatment of benign prostate hyperplasia did not arise.
The earlier synthesis of various 1-(4-aryl-piperazin-1-yl)-3-(2-oxo-pyrrolidin-1-yl/piperidin-1-yl) alkanes and their usefulness as hypotensive and antischemic agents is disclosed in unpublished Indian patent applications DEL 496/95 (Mar. 3, 1995), DEL/500/95 (Mar. 21, 1995) and DEL/96/96 (Mar. 29, 1996) by the inventors herein. These compounds had low xcex11-adrenergic blocking activity (pKixcx9c6 as compared to  greater than 8 of the known xcex11-antagonists such as prazosin), and practically no adrenoceptor sub-class selectivity for xcex11A vs. xcex11B or xcex11D adrenoceptors. It has now been discovered that structural modification of these compounds from lactam to dioxo compounds, i.e., from 2-oxopyrrolidin to 2,5-dioxopyrrolidin and 2,6-dioxopiperidine, enhances the adrenoceptor blocking activity, and also greatly increases the selectivity for xcex11A in comparison to xcex11B-adrenoceptor blocking activity, an essential requirement for compounds to be good candidates for treatment of BPH.
An object of the present invention, therefore, is to provide novel arylpiperazine derivatives that exhibit significantly greater xcex11A-adrenergic blocking potency than available with the known compounds in order to provide specific treatment for benign prostatic hyperplasia.
It is also an object of the invention to provide a method for synthesis of the novel compounds.
It is a further object of the invention to provide compositions containing the novel compounds which are useful in the treatment of benign prostatic hyperplasia.
The above-mentioned objectives are achieved by a novel class of piperazine derivatives of general Formula I below 
wherein Y is O or S; Q,X, Z and Zxe2x80x2 are independently CH or N; m=0-3; n=0-4; R1, R2 are independently selected from: H, F, Cl, Br, OCH3, OC2H5, OCH2CF3, SCF3, CH3, C2H5, CF3, isopropyloxy, and cyclopropyl; R3 is H, R6, OH or OR6; R6 is a substituted or unsubstituted alkyl chain containing 1-6 carbon atoms; and R4, R5 are H, C1-3 alkyl, substituted or unsubstituted phenyl, or a 5-membered spiro ring. Preferably, R1 is H, R2 is H, Cl or CF3, R3, R4, and R5=H, Y=O and Q=CH when m=0 and n=1; or R1 is H, R2 is OCH3, R3, R4 and R5=H, Y=O and Q=CH when m=0 and n=2.
Compounds within the scope of Formula I but having the structure of Formula II below 
wherein n, X, Z, Zxe2x80x2 Rxe2x80x21, R2 and R3 are as defined for Formula I, and wherein mxe2x80x2=1-4, are preferred as selective and potent xcex11A-adrenoceptor antagonistic activity over the xcex11B- and xcex11D-adrenoceptors. In Formula II, preferably R1 is H, R2 is H, Cl or CF3, and R3 is H when mxe2x80x2=1 and n=1; or R1 is H, R2 is OCH3, and R3 is H when mxe2x80x2=1 and n=2.
The present invention also provides pharmaceutical compositions for the treatment of benign prostatic hyperplasia These compositions comprise an effective amount of at least one of the above compounds of Formula I, or preferably of Formula II, and/or an effective amount of at least one physiologically acceptable acid addition salt thereof, with a pharmaceutically acceptable carrier.
An illustrative list of particular compounds of the invention is given below:
Compound No. Chemical Name
1. 1-[4-(4-Fluorophenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
2. 1-[4-(2-Methoxyphenyl)piperazin-1-yl]3-(2,5-dioxopyrrolidin-1-yl)propane
3. 1-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
4. 1-[4-(2-Pyridyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
5. 1-[4-(3-Chlorophenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
6. 1-[4-(2-Pyrimidyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
7. 1-[4-(3,4-Dimethylphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
8. 1-[4-(Phenylpiperazin)-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
9. 1-[4-(2-Methoxyphenyl)piperazin-1-yl]-4-(2,5-dioxopyrrolidin-1-yl)butane
10. 1-[4-(2-Methoxyphenyl)piperazin-1-yl]-2-(2,5-dioxopyrrolidin-1-yl)ethane
11. 1-[4-(3-Methoxyphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane
12. 1-[4-(4-Methoxyphenyl)piperazin-1yl]-3-(2,5-dioxopyrrolidin-1yl)propane
13. 1-[4-(2-Methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane
14. 1-[4-(4-Fluorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1yl)propane
15. 1-[4-(4-Chlorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1yl)propane
16. 1-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane
17. 1-[4-(2-Fluorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane
18. 1-[4-(2-Methylphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1yl)propane
19. 1-[4-(2-Pyridyl)piperazin-1-yl)-3-(2,6-dioxopiperidin-1-yl)propane
20. 1-[4-(3-Chlorophenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane
21. 1-[4-(3,4-Dimethylphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1yl)propane
22. 1-[4-(2-Pyrimidyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane
23. 1-[4-(3-Methoxyphenyl)piperazin-1yl]-3-(2,6-dioxopiperidin-1-yl)propane
24. 1-[4-(4-Methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane
25. 1-[4-(2-Methoxyphenyl)piperazin-1yl]-4-(2,6-dioxopiperidin-1yl)butane
26. 1-[4-(2-Methoxyphenyl)piperazin-1yl]-3-[2,5-dioxo-3-phenyl-pyrolidin-1-yl]propane
27. 1-[4-(Phenyl)piperidin-1-yl]-3-[2,5-dioxopyrolidin-1-yl]propane
The compounds of the present invention may be prepared by one of the reaction sequences (Schemes I, II and III) shown below to yield compounds of Formula II with the R1, R2, R3, R4, R5, R6, m, n, Z, Zxe2x80x2, Q and Y groups as defined above. The starting materials for Schemes I, II and III may be suitably adapted to produce the more general compounds of Formula I.
Scheme-I
Scheme-I shows the synthesis of compounds of the Formula II in which R1, R2, R3, R4, R5, R6, mxe2x80x2, n, Z, Zxe2x80x2, Q, X, and Y are as defined earlier. The preparation comprises condensing xcex1,xcfx89)-dicarboximides of Formula III with 1-(4-arylpiperazin-1-yl)-xcfx89-chloroalkanes of Formula IV, in the presence of a base and an organic solvent at a temperature ranging from 80-150xc2x0 C. for a period varying between 8-24 hours to produce the corresponding 1-(4-arylpiperazin-1-yl)-xcfx89-[-(xcex1,xcfx89-dicarboximido)]alkanes of thee Formula II where R1 and R2 have the meanings given above. Phase transfer catalysts, preferably tetrabutylammonium bromide, are particularly useful in catalysing the reaction. 
Scheme-II
The compounds of Formula II can also be prepared by condensation of the piperazines of the Formula V with the anhydrides of Formula VI wherein R1, R2, R3, Y, Z, Zxe2x80x2, X, and mxe2x80x2 are as defined above. 
Scheme-III
The compounds of Formula II can also be prepared by alkylation of the xcex1,xcfx89-dicarboximide moiety with xcex1,xcfx89-dihaloalkanes followed by condensation of 1-(xcfx89-haloalkyl)dicarboximide thus obtained (Formula VII) with 1-arylpiperazines (Formula VIII) as shown below, wherein R1, R2, R3, Y, Z, Zxe2x80x2, X, mxe2x80x2 and n are as defined above. The reaction is preferably carried out in the presence of a base and an organic solvent at a temperature ranging from 60-100xc2x0 C. for a period varying between 10-24 hours to produce the corresponding 1-(4-arylpiperazin-1-yl)xcfx89-[N-(xcex1,xcfx89-dicarboximido)]alkanes of Formula II. Phase transfer catalysts, more preferably tetrabutylammonium bromide and potassium iodide, are useful in catalysing the reaction. 
In the above Schemes, where specific bases, acids, solvents, phase transfer catalysts, etc., are mentioned, it is to be understood that other acids, bases, solvents, phase transfer catalysts, etc., known to those skilled in the art may also be used. Similarly, the reaction temperature and duration of the reactions may be adjusted according to the desired needs.
The starting piperazines of the Formulas IV, V and VIII are known in the art and may be synthesized by the procedures described in Kiritzy, J. A., et al., J. Med. Chem., 1978, V. 21, p. 1301; U.S. Pat. No. 3,637,705 (Abbott, 1972); FR 2,179,491 (1973); Aggarwal S. K., et al., Ind. J. Chem., 1982, V.21B, pp. 435-439; and U.S. Pat. No. 2,922,788 (Parcell, 1960).
The affinity of the compounds of the invention for each subtype of xcex1-adrenoceptor can be assessed by receptor binding assays (RBA""s) described in the examples given below. It should be noted that the identification and characterization of the foregoing receptors is still in progress and that their types and subtypes are subject to review and refinement.
Receptor binding and in vitro functional assay studies described below indicated that the compounds of the present invention possess selective and potent xcex11A adrenoceptor antagonistic activity over the xcex11B and xcex11D adrenoceptors. The present invention also provides a method to demonstrate the selective affinity of the compounds for prostatic tissues over vascular tissues. Further, the examples presented below describe a method to treat BPH in mammals wherein the test compounds alleviated pressure at dosages which did not result in significant change in blood pressure. Several of the compounds of present invention demonstrated manifest selectivity for prostatic tissues in comparison to known compounds, such as terazosin, doxazosin, etc. The compounds of the present invention also lowered the blood pressure with prolonged duration of action. The compounds of the present invention have been demonstrated to be useful for treating warm blooded animals and mammals. These compounds can be administered orally or parenteraly in suitable pharmaceutical compositions.
Preferred compounds of the invention are 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,5-dioxopyrrolidin-1-yl)propane (Compound No. 2), 1-[4-(2-methoxyphenyl)piperazin-1-yl]-4-(2,5-dioxopyrrolidin-1-yl)butane (Compound No. 9), and 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-(2,6-dioxopiperidin-1-yl)propane (Compound No. 13).
Pharmaceutically acceptable, non-toxic, acid addition salts of the compounds of the present invention having the utility of the free bases of Formulas I and II may be formed with inorganic or organic acids, by methods well known in the art and may be used in place of the free bases. Representative examples of suitable acids for formation of such acid addition salts are malic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylene salicylic, methanesulfonic, ethane disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfamic, phosphoric, hydrobromic, sulfuric, cyclohexylsulfamic, hydrochloric and nitric acids.
The present invention also includes within its scope prodrugs of the compounds of Formulas I and II. In general, such prodrugs will be functional derivatives of these compounds which are readily converted in vivo into the defined compounds. Conventional procedures for the selection and preparation of suitable prodrugs are known.
The invention also includes the enantiomers, diastereomers, N-oxides and pharmaceutically acceptable salts of these compounds, as well as metabolites having the same type of activity. The invention further includes pharmaceutical compositions comprising the molecules of Formula I and II, or prodrugs, metabolites, enantiomers, diastereomers, N-oxides, or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable carrier and optionally included excipients.
In yet another aspect, the invention is directed to methods for selectively blocking xcex11A receptors by delivering in the environment of said receptors, e.g., to the extracellular medium (or by administering to a mammal possessing said receptors), an effective amount of the compounds of the invention.